Prostate cancer is the most commonly diagnosed neoplasm in men. The American Cancer Society estimates that 200,000 new cases of prostate cancer will be diagnosed in 1994, resulting in 38,000 deaths. The use of prostate-specific antigen (PSA), as a diagnostic agent, has been the most significant advance in prostate cancer diagnosis. PSA is an androgen-dependent serine protease produced by prostatic epithelial cells. Elevation of the serum PSA level is indicative of malignancy, yet it is important to realize that the test is not specific for cancer. PSA is also increased with benign prostatic hyperplasia, prostatitis, and trauma.
Present day therapeutic regimens for prostate cancer include radical prostatectomy, radiation therapy, androgen deprivation, and chemotherapy. In radical prostatectomy, the entire prostate, the seminal vesicles, the ampulla of the vas deferentia, and the overlying fascia are removed.
Radiation therapy includes both external and brachytherapy.
Radiation therapy is administered by exposing the patient to the beam of a linear accelerator or by implanting a radioisotope into the prostate gland.
Standard treatment for metastatic prostate cancer is androgen deprivation, achieved nonsurgically through interruption of testosterone production by the testis. Hormonal manipulation can be accomplished in a number of ways. The principal androgen for male reproductive function that affects prostate growth is testosterone. Luteinizing hormone-releasing hormone (LHRH) agonists are believed to inhibit LH release, which in turn inhibits testosterone levels, through a deregulation mechanism after an initial dramatic rise in LH production. LHRH agonists are often combined with nonsteroidal anti-androgens during the first 1 or 2 weeks of therapy to prevent this "flare" phenomenon with exacerbation of symptomatic disease. The expense of these agents limits their use.
Although use of nonsteroidal androgen antagonist is theoretically appealing, application is limited by the fact that androgen ablation does not impart a durable response and virtually all patients progress to an androgen refractory state with a median survival of twelve to eighteen months (C. Huggins and C. V. Hodges, Cancer Res 1,293 (1941)).
Further, testosterone and dihydrotestosterone bind intracellular receptors which limits its use in prostate cancer. Estrogens, such as diethylstilbestrol, can suppress LH production and inhibit androgen activity on a cellular level. These agents are quite effective in achieving androgen deprivation and are very inexpensive, but the potential of estrogens to increase the risk of thromboembolic cardiovascular disease in males has limited their use in recent years.
Chemotherapy has been of limited use in the management of disseminated disease. No effective agent has been identified as yet. Recently, investigators have evaluated the ability of suramin to inhibit the growth of prostate cancer. Response rates of 50% have been reported, although nearly all responses were partial. Duration of response is limited and toxicity is severe and common.
In the last few years, several new approaches for treating advanced neoplasms have been proposed, including that of gene therapy (S. U. Shin, Biotherapy 3, 43 (1991); H. R. Hoogenboom, U. C. Raus, G. Volckaert Biochimica et Biophysica Acta 1996, 345 (1991); S. Kunyama et al., Cell Structure and Function 16, 503 (1991); Z. Ram et al., Cancer Research 53, 83 (1993); R. G. Vile and I. R. Hart, Cancer Research 53, 962 (1993); J. A. Roth, Seminars in Thoracic and Cardiovascular Surgery 5, 178 (1993)).
The PSA gene sequence is known (Riegman P. H. J., Klaassen P., Korput J. A. G. M. van der, Romijn J. C., Trapman J. 1988 Molecular cloning and characterization of novel prostate antigen cDNAs. Biochem Biophys Res Commun 155:181-188; Riegman P. H. J., Vlietstra R. J., Korput J. A. G. M. van der, Romijn J. C., Trapman J. 1989 Characterization of the prostate-specific antigen gene: a novel kallikrein-like gene. Biochem Biophys Res Commun 159:95-102; Riegman P. H. J., Vlietstra R. J., Klaassen P., Korput J. A. G. M. van der, Romijn J. C., Trapman J. 1989 The prostate-specific antigen gene and the human glandular kallikrein-1 gene are tandemly located on chromosome 19. FEBS Lett 247:123-126; C. Lee et al., Prostate 9, 135 (1986); P. Schulz et al., Nucleic Acids Research 16, 6226 (1988); T. Y. Wang and T. P. Kawaguchi, Annals of Clinical and Laboratory Science 16, 461 (1988); D. W. Chan et al., Clinical Chemistry 33, 1916 (1987); L. A. Emtageet et al., British Journal of Urology 60, 572 (1987)).
The PSA promoter has been cloned by Riegman et al., (P. H. Riegman et al., Molecular Endocrinology 5, 1921 (1991)) and four protein binding subregions in this DNA fragment have been identified. An androgen-responsive element (ARE) was defined and has shown androgen responsiveness in COS cells, which are monkey kidney cells, cotransfected with the androgen receptor gene. To date, the tissue specificity of the PSA promoter has not been shown in prostate cells (P. H. Riegman, et al.)
Another study was done which utilized tissue-specific PSA promoter to drive a thymidine kinase (TK) gene that can convert the anti-viral agent acyclovir into a toxic metabolite. In this study, androgen-dependent (e.g., LNCaP), AI(C4, C4-2, DU-145, PC-3), and naive cells (e.g., WH and Hela cells) were infected with either a long PSA promoter (1600 bp) or short PSA promoter (630 bp) luciferase construct. The study showed that a long PSA promoter (1600 bp) at least 10-fold more potent than the short PSA promoter is better than short PSA promoter (630 bp) in inducing luciferase activity. Apparently, the long PSA promoter is better than the short PSA promoter in inducing luciferase activity. To date, the tissue specificity of the PSA promoter has not been characterized in prostate cells.